Molecularly Imprinted Polymer as an Eco-Compatible Nanoreactor in

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Molecularly imprinted polymer as an eco-compatible nanoreactor in multi-component reactions: a remarkable synergy for expedient access to highly substituted imidazoles Ahmad Shaabani, Ronak Afshari, Seyyed Emad Hooshmand, and Mina Keramati Nejad ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.7b02741 • Publication Date (Web): 04 Sep 2017 Downloaded from http://pubs.acs.org on September 4, 2017

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ACS Sustainable Chemistry & Engineering

Molecularly imprinted polymer as an eco-compatible nanoreactor in multi-component reactions: a remarkable synergy for expedient access to highly substituted imidazoles Ahmad Shaabani∗, Ronak Afshari, Seyyed Emad Hooshmand and Mina Keramati Nejad Faculty of Chemistry, Shahid Beheshti University, Daneshjou Boulevard, Tehran, Iran G. C., P. O. Box 19396-4716 ∗ Corresponding author. Tel.: +982129902800; e-mail: [email protected] Abstract: In this paper, an eco-compatible molecularly imprinted polymer (MIP) nanoreactor which synthesized via miniemulsion polymerization has been designed and its catalytic activity investigated in multi-component reaction transformations for the first time. The synthesized MIP nanoreactor was characterized by means of Fourier transform infrared, thermogravimetric analysis, differential scanning calorimetric, scanning electron microscopy, transmission electron microscopy and dynamic light scattering. The imidazole template-derived sites created within a polymeric matrix allow MIP nanoreactors to directly catalyze the reaction and conduct to the target molecule. The results show the applicability of MIP nanoreactors in a one-pot expeditious synthesis of tri- and tetrasubstituted imidazole derivatives via pseudo-four and four-component

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reactions with excellent yields and purities. In addition, biocompatibility and cytotoxicity of MIP nanoparticles were examined and no obvious adverse effects on the viability of human fibroblast (HDF) cells were observed. This green and facile catalytic route has an easy set-up and the products are easily isolated without tedious purification such as aqueous work-up or chromatography in high purity. Meanwhile, MIP nanoreactors showed admirable potential in reusable catalysis recycled several runs without losing significant activities. Keywords: Molecularly imprinted polymer, Nanoreactor, Heterogeneous catalyst, Multicomponent reaction, Imidazole, Heterocyclic chemistry.

Introduction The nature, with no doubt, is the best creator which inspires us for creating the symphony of high performance biomimetic artificial constructions that are meant to overcome many of the human obstacles. One of these obstacles is irrecoverable “time”. The humans have always believed that time is a valuable factor in each activity. Accordingly, an attitude to saving time has been driving force for many inventions throughout the history of science.1 In this sense, in chemistry, the development of efficient catalysts for reducing the time of the principal reactions is a hot field for the synthesis of organic and medicinal compounds in recent years.2 Besides conventional catalysts such as Lewis or Bronsted acids or bases, nowadays nanocatalysts such as supported catalysts,3 metal organic frameworks4 or zeolite,5 ionic liquids,6 and polymer-based catalysts7 as well as enzymes8 have been exhibited a new class of catalysts for many of the organic and inorganic transformations. In the new generation of catalysts besides basic and acidic functional groups the other factors play a key role for catalytic activity such as a hole theory or cavity effects, surface contact increasing, deep hydrogen bonding and etc.9-11


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Molecular imprinting technology (MIT) is a considerable technique for the polymer networks synthesis with high specific memorized cavities for a given compound that retention mechanism involved is based on molecular recognition.12-14 The elegance of molecular imprinting and recognition is reminiscent of psychological phenomena in nature and spurring many of the organic scientists to mimic it as enzyme-mimetic catalytic systems.15 In the procedure, the target organic structure acts as the template, and then the monomers and cross-linker are arranged (covalently or noncovalently) around the template and polymerized to form a cast-like shell. After polymerization process, the template is removed and a snapshot of the network is taken so that the resultant molecular assembly specifically binds this template and cavities show a great complementary with the shape and the functional group positions of template. Subsequently, a molecular memory with the ability to rebinding with the template with high selectivity is created in the polymer matrices.16-18 Similar to antibody catalysts these enzymatic active sites in the three-dimensional molecularly imprinted polymer (MIP) networks can act as a neoteric generation of task specific nanoreactors for catalyzing the reaction through the template molecule.19 These enzyme-mimic nanoreactors accelerate the reaction rates by their free cavities which are capable to encapsulating reagents and creation of high local pressure through cavitation effects.20 In this case, first priority is the imprinting of the cavity with the final product of the reaction. Next, precursors are entered to the shape-memorized cavities so that a reaction can convert it into the desired product.21 In addition, it is worth noting that MIPs synthesis is also relatively cheap with easy workup,22 making them an appropriate industrial alternative for traditional catalytic systems. In spite of numerous examples that have been reported for applications of molecular imprinting in drug and gene delivery systems,23 molecular recognition24-25 adsorption26-27 and extraction,28-29



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the area of catalysis has been less exploited. The utilization of enzyme-mimetic MIPs as a catalyst was investigated previously in the reactions such as Diels-Alder,30-31 hydrolyses,32 dehydrofluorination,33 carbon-carbon bond formation34 cross-aldol reaction,35 Huisgen 1,3dipolar cycloaddition,36 concomitant reaction of hydrolysis along with reduction37 and control peptide disulfide bridge formation.38 Based on our literature survey; there is no report yet available on the synthesis of multi-component reactions (MCRs) via MIP nanoreactors. MCRs are one-pot types of reactions made from three or more substrates which can lead to direct access to target products with inherent molecular diversity and atom economy. Nowadays, these efficient synthetic routes have been applied for rapid access to complex molecular architectures, especially for heterocycles,39 natural products,40 polymers41 and macrocyclic compounds.42 Also, MCR approaches are using for medicinal applications and drug discovery.43 Since the MCRs are highly convergent processes and MIP structures contain shape memorized cavity with high binding affinity for functional groups involved, it has been postulated that this virtually innocuous means of activation could efficiently catalyze MCRs. On the other hand, high pressure activation is presented as a potent organic synthetic strategy.44 Therefore, a coupling of high pressure with shape-memorized cavities in MIP nanoreactor can accelerate the rate of the MCRs which inherently accompanied with entropy reduction in transition state.45 Inspired by this enzyme-mimetic mechanism46 and encouraged by our continued interest in developing of novel catalyst systems47-49 and MCRs methodology,50-54 we introduce MIP nanoreactors as an applicable eco-compatible heterogeneous nanocatalyst in MCR. In recent years, development of imidazole derivatives via MCR protocols as one of the most significant categories of nitrogen-containing heterocyclic compounds has gained widespread attentions because of high biological activity.55 Imidazole core structures have been presented in diverse


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biologically active systems such as histidine and the related hormone histamine. Noteworthy, imidazole scaffolds are present in many drugs like clotrimazole, losartan and eprosartan.56 For this purpose, one pot and step economic synthesis of pharmaceutically interesting diverse kind of imidazole derivatives via pseudo-four and four-component reaction have been investigated to expand the application scope of these tailor-made high-performance polymer networks (Scheme 1).

Scheme 1. Schematic plan of MIP preparation and its catalytic application as a nanoreactor in MCRs

Experimental



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Materials and methods Methacrylic acid (MAA) was purchased from Merck and distilled before use. AIBN was also obtained from Merck and recrystallized from methanol prior to usage. The other materials were purchased from Merck and Aldrich without necessity for further purification. Synthesized products were analysed using a Varian 3900 GC. Fourier transform infrared (FT-IR) spectrum was recorded on a Shimadzu IR-470 spectrometer. Thermogravimetric analysis (TG/DTG) was carried out using Perkin-Elmer TGA, STA1640 with heating rate of 10 °C min−1 in a nitrogen atmosphere. The differential scanning calorimetric (DSC) analysis was performed on a METTLER TOLEDO DSC 1 with heating rate of 10 K/min in a nitrogen flow. Field emission scanning electron microscopy (FE-SEM) analyses were performed by Philips XL-30 ESEM. Transmission electron microscopy (TEM) was carried out using Philips CM30. Dynamic light scattering (DLS) was used for polydispersity index (PdI) measurement by Zetasizer Nano ZS90, Malvern Instruments. Melting points were measured on an Electrothermal 9100 apparatus. 1H and

13

C NMR spectra were obtained at 300.13 and 75.47 MHz in DMSO-d6 on a BRUKER

DRX-300 AVANCE spectrometer. Synthesis of 2,4,5-triphenyl-4,5-dihydro-1H-imidazole as a template (4a) This compound was synthesized according to the previously reported method.57 In a 50 ml flask, benzil (1.05 g, 5.00 mmol), benzaldehyde (0.53 g, 5.00 mmol) ammonium acetate (0.92 g, 12.00 mmol) and 10 mol % of InCl3.3H2O were mixed in methanol (15 ml) and stirred for 10 hour at room temperature. After completion of the reaction as indicated by TLC, the reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate (2 * 15 ml). The organic phase was dried with anhydrous Na2SO4 and recrystallized from ethanol for final purification.


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Synthesis of MIP nanoreactors The molecularly imprinted nanoreactors for the imidazole (4a) as a template was prepared via miniemulsion polymerization.58 In brief, methacrylic acid (MAA) (0.34 g, 4.00 mmol) as a functional monomer, ethylene glycol dimethacrylate (EGDMA) (3.17 g, 16.00 mmol) as a crosslinker and hexadecane (0.30 ml) as a hydrophobic agent were mixed in a three-neck roundbottom flask. Then the imidazole (4a) (0.298 g, 1 mmol) and azobisisobutyronitrile (AIBN, 0.30 mmol) as an initiator were added to the mixture and sonicated for 30 min till the interaction of monomers and imidazole (4a) were occurred. Afterward, 15 mg of the sodium dodecyl sulfate (SDS) were dissolved in 30 ml deionized water and added dropwise to the mixture using a homogenizer at 24,000 rpm for 5 minutes. Then the emulsion was degassed via dry N2, submerged in 70 oC water bath and stirred for 24 h until the polymerization were completed. After completion of the polymerization, the synthesized nanoparticles were separated by centrifuging for 15 min at 21,000 rpm, washed three times with deionized water for removal of unreacted reagents and dried overnight in oven at 50 oC. The imidazole (4a) was removed by batch-mode solvent extraction upon 40 ml of ethanol including 10% acetic acid (v/v) for five times, detected by thin layer chromatography (TLC). Finally, MIP nanoparticles (NPs) were washed with acetone and dried at 50 ºC. Besides, the non-imprinted polymers (NIPs), as a control polymer, were synthesized through the same procedure but without the presence of the imidazole (4a). General procedure for the synthesis of trisubstituted imidazoles In a pilot experiment, benzaldehyde (1.00 mmol), benzil or benzoin (1.00 mmol), ammonium acetate (0.19 g, 2.50 mmol) and MIP NPs (0.04 g) were mixed and heated at 120 °C under solvent-free conditions for 20-50 min. TLC (hexane: ethyl acetate) was used for monitoring the



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process of the reaction. After the completion of the reaction, 5 ml acetone was added and the catalyst separated by filtration. The synthesized compounds were further purified, if necessary, by recrystallization from acetone–water 9:1 (v/v) to give desired trisubstituted imidazoles. General procedure for the synthesis of tetrasubstituted imidazoles In a brief, a mixture of benzil (1.00 mmol), anilines (1.00 mmol), benzaldehyde (1.00 mmol), and ammonium acetate (0.08 g, 1 mmol) in the presence of MIP NPs (0.04 g) was stirred at 110 °C under solvent free conditions for 40-60 min. Completion of the reaction was monitored by TLC (hexane: ethyl acetate). Then, the reaction mixture was dissolved in ethanol (5 mL) and the MIP NPs were separated by filtration. If necessary, the obtained product was recrystallized from ethanol-water 7:1 (v/v) to produce the pure tetrasubstituted imidazoles. Biocompatibility tests For biocompatibility test, the cytotoxicity of MIP nanoparticles at different concentrations of 10, 20, 50 µgmL-1 was determined by MTT assay following the same procedure as previous works.59-60 Initially, the human fibroblast (HDF) cells which were obtained from Pasteur Institute of Iran were seeded into 96-well plates (1 * 104 cells/well) using 100 ml RPMI medium containing 10% fatal bovine serum (FBS) and 1% antibiotics then incubated in a humidified 5% CO2 balanced air incubator at 37 oC for 24 h. In continuation, the medium was replaced with 100 mL of culture medium containing MIP nanoparticles with different concentrations, except control cells. After incubated at 37 oC for 24 and 72 h, the medium was replaced with 100 mL of MTT solution with 0.5 mgmL-1 concentration. After continuous incubation for 4 h, the absorbance of the solutions was measured at a wavelength of 545 nm using an Elisa plate reader (STAT FAX 2100, USA). Each sample was analyzed in triplicate.


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Results and discussion Molecular imprinting, known as “key-to-lock” process, provides a straightforward route to the synthesis of materials with molecular recognition sites comparable to natural enzymes, but with improved properties due to their stable cross-linked structure.16 This fact that MIPs withstand more aggressive conditions and they function in organic solvents, under acidic or basic conditions, elevated high temperature and pressure makes them promising catalysts.33 Generally, this system could serve as a great candidate for wide ranges of multi-component reactions with various reaction conditions. Therefore, we investigated the catalytic ability of MIP in the MCR that conducted to imidazole derivatives under solvent-free conditions. For this purpose, initially, the template must be chosen. As it is reported previously, for obtaining catalytically active imprinted materials the template should be structurally in accordance with the substrate, the transition state (transition state analogue, TSA) of a reaction, or with the product.21 Meanwhile, the more studied approaches to catalysis by MIPs reaching out the TSA analogues. In this case, the recognition cavities of the 3-dimensional polymer networks can stabilize the formation of the transition state, whereby conducted transition energy requirement to the lower amount which amplified the rate of the reaction.61 Since it is impossible to prepare and separate the TSA of imidazole scaffold in this reaction we choose the product analogue of the reaction, imidazole (4a), as a template through non-covalent imprinting protocol. Non-covalent interactions show easiness of the preorganization and imprinting steps.62 Then MAA and EGDMA as functional monomer and crosslinker were mixed with imidazole (4a) and formed the in situ complex by non-covalent interactions. MAA is a good candidate for this polymerization due to the polar carboxylic acid group’s ability to interact with –NH segment of



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imidazole scaffold through hydrogen bonding and electrostatic forces which increased efficient interaction of functional monomers with template molecules, also the better selectivity arise from the steric hindrance of methyl group in MAA is a vital factor. Continuously the miniemulsion polymerization process was performed for creating the molecularly imprinted nanoparticles. The most important reason for choosing this kind of polymerization is the ability of miniemulsion method to provide mono-disperse nano-size reactors with an extended surface area for template uptake in a single-step procedure without need of hazardous organic solvents which open a sustainable gateway toward the green polymerization.63 Subsequent extraction of the imidazole (4a) with ethanol then created the recognition sites in the polymer matrix that correspond to imidazole (4a) in size, shape and arrangement of the complementary functional sites.21 The schematic representation of imprinting and removal of the imidazole (4a) from the imprinted polymer was shown in Scheme 2.


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Scheme 2. General mechanism for the preparation of molecularly imprinted nanoreactors for imidazole (4a) After the removal of imidazole (4a), polymers with tailored cavities were obtained, which structure and position of functional groups were predetermined by the chemical entity of imidazole (4a). FT-IR spectroscopy was performed to confirm the chemical structure of MIP after removal of template (Figure 1). The MIP shows clear stretching vibration at 3471 cm-1 corresponds to the of –OH bond. The peak at 2977cm-1 show asymmetric stretching vibration of CH2 group. While, C=O stretching vibration and the bending vibrations are observed in 1730 and 1469 cm-1, respectively. Furthermore, the peaks at 1263 and 1159 cm-1 are attributed to the symmetric and asymmetric stretch bonds of C-O. Finally, the peak at 968 cm-1 is related to the presence of vinylic C-H bonds.



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Figure 1 FT-IR spectra of leached MIP nanoreactors One of the important factors for selecting a suitable catalyst for the reaction is thermal behaviour and stability especially in the solvent-free conditions that need heating. In this sense, TG/DTG experiment is carried out by heating MIP NPs up to 600 °C under N2 at a heating rate of 10 °C min-1 (Figure 2a). The TG/DTG thermogram showed the initial mass of approximately 7 wt% below 100°C attributed to moisture and solvent evaporation from polymer structures. Obvious weight loss appered in the temperature range of 350–480 °C, corresponded to the decomposition of polymeric matrix and remained stable about 490 °C with about 97% total weight loss. Overall, the result showed that the MIP nanoreactors can be remarkably stable at temperatures in excess of 340 oC. In a following investigation, to gain more insight about the thermal characterization of MIP networks, DSC analysis was performed from 30 to 200 °C (Figure 2b). In the first run, the MIP was heated to 180 °C and exihibited an endothermic peak for the evaporation of the solvent and moisture at about 100 °C then the MIP was cooled down. As it can be seen in the cooling curve, there is no evidance of any indexed endothermic peak at that temperature. Also, the glass


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transition temperature was determined to be 84.14 °C from the second heating run after the first run of heating up to 180 °C and cooling to 25 °C. The DSC result of MIP nanoreactors confirmed that the initial weight loss that observed in TG/DTG curve was attributed to the remained solvent and moisture which was trapped in the 3D structure of the polymer networks. Also, these nanoparticles have a good thermal stability more than 200 °C, that makes it a great candidate for catalyzing processes that need heating.



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Figure 2. TG/DTG plot (a) and DSC thermogram (b) of MIP nanoreactors In a follow-up investigation, the morphology of polymeric nanoreactors was investigated using SEM and TEM (Fig. 3). As the SEM image reveal the MIP NPs show high uniformly sized nanospheres with a narrow particle size distribution (Figure 3a). The TEM image exhibit that


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mono-disperse spherical and uniform particles with an average mean diameter of 230 nm were formed (Figure 3b). Also, the TEM image represents the nanoparticles with an inner space that appear darker than the outer cortex. It can be concluded from the results that MIP scaffolds were accessed by the reactants so it can be rendition as a nanoreactor. Since, the main objective of nanocatalysis synthesis is to produce catalysts with extremely high selectivity and activity, low-energy consumption, and long lifetime and this can be achieved by controlling the size, shape and spatial distribution of the nanoparticles,64 therefore, hydrodynamic diameter of the particles was measured with DLS analysis (Figure 3c). The sharp DLS measurement curve demonstrated the great efficiency of miniemulsion polymerization process for the synthesis of narrow nano-size MIP particles. The data revealed that the average hydrodynamic particle diameter and polydispersity index (PdI) were 280 nm and 0.183, respectively.



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Figure 3. SEM (a), TEM (b) image and particle size distribution (c) of MIP nanoreactors To assess the biocompatibility, the cytotoxicity of MIP nanoparticles (with a concentration of 10, 20 and 50 µgmL-1) in contact with human fibroblast (HDF) cells is measured within 24 and 72 h after incubation. Based on the protocols for biological evaluation of medical devices, the exposed materials are to be considered non-cytotoxic and biocompatible if the percentage of a viable cell is equal to or greater than 70% of the untreated control (ISO 10993-5:2009). The viability of HDF cells in the presence of 10, 20 and 50 µgmL-1of MIP nanoparticles is very close to the control sample which was excluded from Figure 4. Even the sample at 50 µgmL1

concentration, shows more than 85% of cell viability. Based on the above mentioned ISO

standard this high cell viability confirms the biocompatibility of the synthesized nanoreactor. Based on our literature scanning, there is no report yet available for the investigation of


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biocompatibility of the catalytic system in this progress. Even most of the catalytic reports65-69 for the synthesis of this biologically active heterocycles are typically based on the presence of the wasting material supports, hazardous metals and utilization of toxic organic solvents. According to the results, MIP nanoparticles did not have any toxic extract or degradation products in this concentration range and prove great biocompatibility of the nanoparticles even after 72 h. This finding demonstrates that the introduced nanoreactor could also be applied as an effective, safe and sustainable catalyst for the synthesis of pharmaceutical and medicinal compounds.

Figure 4. HDF cell viability at different MIP nanoparticle concentrations after 24 and 72 h Ideal multi-component syntheses involve the simultaneous addition of all reactants, reagents, and catalysts at the beginning of the reaction through a single-pot procedure, which cause to complex molecular architectures with high atom economy.70 This type of procedure has been known as “cascade” synthesis. The main benefits of cascade approach include high atom economy, reduction of solvent and waste generated (by-products, catalyst, etc.) caused by



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product isolation and many work-up procedures by diminishing the number of synthetic steps was developed among organic scientist. It has been postulated that synthesized MIP as a nanoreactor and task specific nanocatalyst could lead to rapid system for single pot multicomponent cascade synthesis of imidazoles. For proving this hypothesis, the catalytic activities of MIP nanoreactors were evaluated and the conditions were optimized. The model reaction of benzaldehyde (0.10 g, 1.00 mmol), benzil (0.21 g, 1.00 mmol) and ammonium acetate (0.16 g, 2.10 mmol) catalyzed by MIP nanoreactors was performed for the construction of 2,4,5-trisubstituted imidazole (4a). Likewise, the effects of reaction parameters such as temperature, solvent (exp., water, ethanol, acetonitrile and toluene) and solvent free conditions, amount of catalyst also reaction time on kinetics were investigated in detail. As shown in Table 1, the use of organic solvents or water gave inferior results in both yield and reaction time even though the using of ethanol was relatively satisfactory in both cases. At last but not least, MIP nanoreactor (0.04 g) under solvent free conditions at 120 oC in 20 minutes provided the best results, quantitate yield, in accordance with the hypothesis. Table 1. Optimization of the reaction conditions for access to trisubstituted imidazole derivatives via MIP nanoreactorsa Entry

Solvent

Temperature (oC)

Catalyst (gr)

Yield (%)c

1

EtOH

78

0.01 g

60

2

EtOH

78

0.02 g

77

3

EtOH

78

0.04 g

90

4

EtOH

25

0.04 g

20

5

S.F.

100

0.04 g

88


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a

6b

S.F.

120

0.04 g

Quant.

7

Water

100

0.04 g

Trace

8

Toluene

110

0.04 g

45

9

CH3CN

80

0.04 g

40

Reaction conditions: benzaldehyde (0.10 g, 1.00 mmol), benzil (0.21 g, 1.00 mmol) and ammonium

b acetate (0.19 g, 2.50 mmol) in 30 minutes. Also the reaction was performed under this condition in 20

and 10 minutes with quantitative and 82% yields c Isolated yields.

After optimization of the reaction conditions, we subsequently extended the scope of the present system through MIP as an eco-compatible nanoreactor with a variety of aldehydes as well as diketone compound derivatives to convenient access to a small library of 2,4,5-trisubstituted imidazoles. Various aldehydes containing electron-deficient and electron-rich functional groups were found to react efficiently. Also, diketone compounds such as benzoin and various benzils have been applied to obtain the desired products with excellent yield (Table 2). Table 2. Synthesis of 2,4,5-trisubstituted imidazoles via MIP nanoreactors Entry

Aldehyde

R1

Yields (%)a

Product

Benzil: Quant. 1

Benzaldehyde

H

4a

Benzoin: 98 Benzil: Quant.

2

4-Cl-Benzaldehyde

H

4b

Benzoin: 96 Benzil: Quant.

3

4-NO2-Benzaldehyde

H

4c

Benzoin: 99 Benzil: 97

4

4-CH3-Benzaldehyde

H

4d

Benzoin: 94



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5

1,3-Benzodioxole-4-carbaldehyde

H

4e

Benzil: 94

6

2-Formylphenoxyacetic acid

H

4f

Benzil: 88

7

2-Chlorobenzaldehyde

OMe

4g

Benzil: 99

8

4-(Benzyloxy)benzaldehyde

OMe

4h

Benzil: 93

9

4-(Dimethylamino)benzaldehyde

F

4i

Benzil: 94

a

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Isolated yields

According to the results in Table 2, it is clear the MIP that polymerized around the imidazole (4a), as a task specific template, can robustly play a catalyst role for the synthesis of the other imidazole scaffolds. In this case, the chemical structure of the imidazole (4a) was particularly designed to possibly simulate the chemical geometry of the transition state or an intermediate of this reaction and perform the high binding between the general cavities of product analogue to a transition state of the reaction. Based on the concept of transition state stabilization which catalytically active antibodies have been raised against stable transition state of the reactions known from enzyme catalysis,.71-72 Similarly, the 3-dimensional polymer network of MIP were used to direct the reaction through the decreasing the energy of the transition state. Also acoustic cavitation of MIP and increasing the interaction of trapped reagent molecules in smart shapes caused increased yields of products and reduced the time of the MCRs. Subsequently, due to the importance of fully-substituted heterocyclic rings in organic synthesis and medicinal chemistry also for the examination of selectivity ability of the MIP nanoreactors this catalytic system have been extended for the direct synthesis of tetrasubstituted imidazole derivatives. Initially, for the straightforward access to tetrasubstituted imidazoles, optimization was made in the same fashion. The best conditions were found in solvent-free at 110 °C and 0.04 grams of MIP nanoreactors as the catalyst. In order to extend the scope of this nanoreactors,


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various anilines, benzaldehydes and benzils contain electron-donating and electron-withdrawing substituents perform equally well as substrates for the direct synthesis of the corresponding imidazoles (Scheme 3, 5a-d). As can be seen, the reaction shows well to excellent yields without preparation of any bi-products. Since the tetrasubstituted imidazole has a similar core-skeleton with the template 4a (imidazole scaffold) therefore under the influence of the MIP nanoreactor were obtained with same good yields to the previous reaction. Although, due to the little structure differences in comparison with compound 4a the yield shows a negligible decrease and time of the reaction is taking longer. Scheme 3. Structures and isolated yields of tetrasubstituted imidazoles NH2 O

O Y + R1

NH4OAc

MIP 5a-d 110 oC, 40-60 min

R1 CHO

X

OMe

Br

OMe N

N

5a : 97 %

N

N

5b : 90%

N N

N

N

MeO 5c: 95 %


5d : 92%

OMe


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To gain more insight into the role of the binding sites and shaped memorized cavities of polymer on the catalytic activity of MIP nanoreactors for the synthesis of 2,4,5-trisubstituted imidazoles, the comparison between imprinted and non-imprinted polymer for the model reaction has been done. As is well known, NIP has been synthesized under the same reaction conditions but without participating of the template molecule. The catalytic activity of both MIP and NIP were investigated in the optimum conditions. Although NIP nanoparticles can relatively catalyze this MCR due to the presence of the created pressure, but compared to MIP nanoreactors the desired product was obtained with low yields and purity. But, the entity of shape-memorized cavities integrant with imidazole template in the MIP scaffolds is caused to high selectivity of the MIP nanoreactors in comparison with NIP toward the synthesis of imidazole derivatives. Thus, the memorized sites have to be able to prepare the optimal spatial arrangement geometry which caused to appropriate conformation of reactant and therefore conducted the reaction to take place.21 The total amount of product (4a) obtained with MIP was 1.47 times that of with NIP. On the other hand, these cavities lead to a local high pressure that has a clear effect on the reaction rate because this MCR accompanied by an entropy decrease in the transition state.44, 73 To wrap up the discussion, when pressure and selectivity intermixed together a perfect synergy be created for imidazole derivatives synthesis. Quick access to imidazole derivatives via pseudo-four and four-component reactions with MIP nanoreactors obtained not only lower production costs resulting from atom economy and high convergence, but also increase the eco-compatibility which is the main principle of green chemistry. In addition, the reaction was carried out in single pot and step process by excellent yield and short reaction time. Above all, using MIP as a robust nonreactor caused 100% conversion and quiet product isolation without using particular purification such as


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chromatography. Since this MCR catalyzed with reusable MIP nanoreactors has been carried out under solvent free condition could be improved E-factor and mass intensity as important green chemistry metrics. The comparison between our reaction conditions with previous reports for the synthesis of multisubstituted imidazoles has been established with respect to their yields, temperatures, solvent, and the time of the reaction. As shown in Tables 3 and 4, in comparison with previous works, the reaction yields in nanoreactor increased significantly in short reaction times without need of alternate input energy such as microwave or ultrasonic. This effect can be explained via the cavity effect of the nanoreactor which could enhance the pre-organization of precursors with creating strain inside its cavity. This nanoreactor as heterogeneous catalyst can take place chemical transformations in its high pressure cavities which have ability to encapsulate reactants. It is therefore not too surprising that the integration of the mentioned effects could overcome the energy barrier of MCRs. In addition, compared to other activation modes, high pressure coupled with shape-memorized cavities are a very mild and non-destructive preparation methods.45,

74

Also, it is shown that when catalyst have not used these reactions gave very poor yield or no product at all. Consequently, can infer from all above that synthesized MIP nanoreactors could be a versatile catalysts for the other MCRs that need high pressure for performing the reaction. Table 3. Catalysts performance comparison between the literature and the MIP nanoreactors for the synthesis of 2,4,5-trisubstituted imidazoles Entry

Catalyst

Condition

Time (min)

Yields (%)a

Ref.

1

InCl3.3H2O

MeOH, r.t.

500

82

40

2

Nano silica phosphoric acid

Solvent-free, 140 oC

180

90

75

3

Montmorilonite K10

EtOH, Reflux

90

70

76



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4

Zeolite

EtOH, Reflux

60

80

76

5

L-Proline

MeOH, 60 oC

540

90

77

6

[Hbim]BF4

RTIL, 100 oC

60

95

78

7

Fe3O4–PEG–Cu


30

98

79

8

Diethyl bromophosphate

US, CH3CN, r.t

40

95

67

9

Fe3O4@SiO2-Imid-PMAn

MW(100W), Solvent-free

10

95

80

10

Boehmite nanoparticles

Solvent-free, 120 °C

40

98

81

11

MIP nanoreactors


20

Quant.

a

This work

Isolated yields

Table 4. Catalysts performance comparison between the literature and the MIP nanoreactors for the synthesis of 1,2,4,5-tetrasubstituted imidazoles

Time (min)

Yields (%)a

Ref.


120

90

66

L-Proline

MeOH, 60 °C

510

86

50

3

Fe3O4@chitosan

EtOH, Reflux

120

95

82

4

n-CTW-SAb


40

94

83

5

Fe3O4–PEG–Cu


55

96

52

6

WD/SiO2 c


120

85

84

7

DABCO

t-BuOH, 60-65 oC

720

92

85

8

MIP nanoreactors


40

97

This work

Entry

Catalyst

Condition

1

SbCl5/SiO2

2

a

Isolated yields, b nano-Ceramic Tile Waste-SO3H, c Wells–Dawson heteropolyacid supported on silica

The easy catalyst recycle is one of the advantages for heterogeneous catalysts from the view of green chemistry and industrial interest. The recyclability of the nanoreactor was investigated during the synthesis of 4a (Figure 5). After the reaction completion, the catalyst can be easily


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reused for the next run. For this purpose, nanoreactors were washed with ethanol and distilled water then dried under oven at 60 °C. It was observed that MIP nanoreactors are reusable at least for 4 times without the significant loss in the isolated yield of 4a. As shown in TEM image, after the 4 run, MIP nanoreactors have morphologically remained stable and still has semi-spherical morphology also there is no sign of any particle agglomeration or deformation (Figure 5b). However, its catalytic activity gradually decreased with consecutive runs (100, 98, 90, 84% respectively), and hence the longer reaction times, probably due to occupation or chemical damage of the holes in the polymeric matrices of catalysts.

Figure 5. (a) Reusability of MIP nanoreactors (b) TEM image of recovered nanoreactors after 4th runs



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Conclusion In conclusion, for the first time, it has been shown that molecularly imprinted polymer nanoreactors can be directly applied in multi-component reactions through a one-pot and step economic procedure. The MIP nanoreactors have been demonstrated to possess an excellent yield and high degree of purification towards the synthesis of multi-substituted imidazole derivatives under solvent-free condition. The results obtained from characterizations show that the miniemulsion polymerization can efficiently provide mono-disperse nano-size reactors with free inner space that are stable in high temperatures. Short reaction times, eco-compatibility, being inexpensive and simple manufacture are the most advantages of using MIP nanoreactor. Also, the catalyst was reusable even for four runs without obvious loss of catalytic activity. Since in these enzyme-mimetic nanoreactors two or more reactants could encapsulate in the same cavity and directly orient to complex organic structures, it seemed that MIP nanoreactors could be a great candidate for catalyzing the other MCRs, especially those that have known transition states. In addition, it is important to point out due to the high biocompatibility of this nanoreactor it could be a great candidate for drug design and industrial productions. Associated Content Supporting Information. Spectral data and copies of 1H NMR and

13

C NMR of new

compounds. This material is available free of charge via the Internet at http://pubs.acs.org. Acknowledgments We gratefully acknowledge financial support from the Iran National Science Foundation (INSF), the Research Council of Shahid Beheshti University and Catalyst Center of Excellence (CCE) at Shahid Beheshti University.


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The catalytic activity of eco-compatible molecularly imprinted polymer nanoreactor has been investigated in multi-component reactions for the first time.


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Molecularly imprinted polymer as an eco-compatible nanoreactor in one-pot multi-component cascade reactions toward the direct synthesis of tri- and tetrasubstituted imidazole derivatives 400x200mm (72 x 72 DPI)


Molecularly Imprinted Polymer as an Eco-Compatible Nanoreactor in

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